Histological Subtype Of Breast Cancer Research Articles

Gene expression variation between distinct areas of breast cancer measured from paraffin-embedded tissue cores

BackgroundDiagnosis and prognosis in breast cancer are mainly based on histology and immunohistochemistry of formalin-fixed, paraffin-embedded (FFPE) material. Recently, gene expression analysis was shown to elucidate the biological variance between tumors and molecular markers were identified that led to new classification systems that provided better prognostic and predictive parameters. Archived FFPE samples represent an ideal source of tissue for translational research, as millions of tissue blocks exist from routine diagnostics and from clinical studies. These should be exploited to provide clinicians with more accurate prognostic and predictive information. Unfortunately, RNA derived from FFPE material is partially degraded and chemically modified and reliable gene expression measurement has only become successful after implementing novel and optimized procedures for RNA isolation, demodification and detection.MethodsIn this study we used tissue cylinders as known from the construction of tissue microarrays. RNA was isolated with a robust protocol recently developed for RNA derived from FFPE material. Gene expression was measured by quantitative reverse transcription PCR.ResultsSixteen tissue blocks from 7 patients diagnosed with multiple histological subtypes of breast cancer were available for this study. After verification of appropriate localization, sufficient RNA yield and quality, 30 tissue cores were available for gene expression measurement on TaqMan® Low Density Arrays (16 invasive ductal carcinoma (IDC), 8 ductal carcinoma in situ (DCIS) and 6 normal tissue), and 14 tissue cores were lost. Gene expression values were used to calculate scores representing the proliferation status (PRO), the estrogen receptor status and the HER2 status. The PRO scores measured from entire sections were similar to PRO scores determined from IDC tissue cores. Scores determined from normal tissue cores consistently revealed lower PRO scores than cores derived from IDC or DCIS of the same block or from different blocks of the same patient.ConclusionWe have developed optimized protocols for RNA isolation from histologically distinct areas. RNA prepared from FFPE tissue cores is suitable for gene expression measurement by quantitative PCR. Distinct molecular scores could be determined from different cores of the same tumor specimen.

Glycogen-rich clear cell carcinoma of the breast

BackgroundGlycogen-rich carcinoma of the breast is a rare histological subtype of breast cancer, usually reported to have poor prognosis.Case presentationWe present the case of a 59-year-old woman who underwent a mastectomy for a 3.5 cm clinically palpable left breast carcinoma, originally diagnosed as fibroadenoma on a screening mammogram four years before presentation. Diagnosis of clear cell carcinoma was based on certain histological characteristics of the tumour and immunohistochemical analysis (PAS staining, keratins AE1/AE3, EMA, cytokeratin 7, cytokeratin 20, melanosomes, vimentin, Chromogranin, Synaptophysin, S-100, SMA). No lymph node metastasis was found and as the tumour was ER positive and PgR negative, patient was treated only with an aromatase inhibitor upfront and remains free of disease 48 months now since operation.ConclusionGlycogen-rich clear cell carcinoma of the breast is a rare tumor, its clinical behavior reported to be rather aggressive so far, might varies depending on special characteristics such as low grade and strongly positive ER expression

Impact of hormone replacement therapy on the histologic subtype of breast cancer

Postmenopausal hormone replacement therapy (HRT) is associated with an increase in breast cancer risk, which correlates to the duration of HRT use. We wanted to investigate a possible association between HRT use and the risk of a histologic subtype of breast cancer. From 1995 until 2004, 497 cases of primary ductal, lobular or ductulolobular breast cancer in postmenopausal women were diagnosed at the Department of Gynecology and Obstetrics, University Hospital Basel, Switzerland. The data was derived from patient's records. HRT ever use was defined as HRT use for > or =6 months. Of the 99 cases of lobular cancer 72.7% were invasive lobular cancers, 21.2% were invasive ductulolobular cancers and 6.1% were lobular cancers in situ. Of the 398 cases of ductal cancer, 90.5% were invasive ductal cancers and 9.5% were ductal cancers in situ. Totally 144 women were HRT ever users, and 341 women were HRT never users. HRT status could not be defined in 12 women. HRT ever use was associated with an increased risk for lobular cancer (OR 1.67; 95% CI 1.02-2.73). Also, menopause due to bilateral oophorectomy was associated with an increased risk for lobular cancer (OR 2.42; 95% CI 1.06-5.54). There is evidence that HRT as well as menopause due to bilateral oophorectomy may be associated with an increased risk for lobular cancer. This association is of major clinical relevance, since lobular breast cancer is more difficult to diagnose clinically and radiologically than ductal breast cancer.

Does the Benefit of Sentinel Node Frozen Section Vary Between Patients With Invasive Duct, Invasive Lobular, and Favorable Histologic Subtypes of Breast Cancer?

Although many questions regarding sentinel lymph node (SLN) biopsy in breast cancer have been answered by observational studies and, increasingly, by prospective trials, the role of intraoperative SLN assessment remains a matter of debate. Here we report in detail the results of intraoperative SLN assessment by frozen section (FS), with particular attention to variations in sensitivity and yield by histologic subtype, by tumor size, and by other clinicopathologic parameters. Five thousand two hundred ninety-eight consecutive patients with clinical stage T1-3N0 invasive breast carcinoma had SLN biopsy with intraoperative FS at Memorial Sloan Kettering Cancer Center between 1996 and 2004. We report the results of FS by sensitivity (the proportion of all positive SLN detected by FS) and by yield (the proportion of all FS procedures in which the FS was positive). The sensitivity of FS was 61% overall, was higher for invasive duct (ID) than for invasive lobular (IL) cancers (62% vs. 52%; P = 0.006), and was marginally lower for favorable subtypes (46%; P = 0.26). The yield of FS was 21% overall, with no difference between ID and IL cancers (22% vs. 21%; P = 0.49), and with a substantially lower yield for favorable subtypes (3%; P < 0.001). The yield of FS increased with tumor size for ID and IL cancers (P < 0.001), but not for favorable subtypes. For both ID and IL cancers, the sensitivity and yield of FS were significantly higher with younger patient age, increasing tumor size, and lymphovascular invasion. The yield of FS was <10% for all patients with ID or IL tumors < or =1 cm in size who were older than 60 years of age. Among all FS-positive patients, only 45% were identified by the first FS, whereas 91% were cumulatively identified by the first, second, or third FS. For patients with ID and IL cancers, the overall sensitivity of FS is >50%, but the yield of FS is <10% for individuals > or =60 years of age with T1a/b tumors. Intraoperative FS may not be worthwhile for this low-yield subset, especially for patients with invasive breast cancer of favorable type.

P26 Tumor infiltrating lymphocytes in medullary breast cancer

The need for axillary nodal staging in favorable histologic subtypes of breast cancer is controversial.Patients with clinical stage T1-2, N0 breast cancer were enrolled in a prospective, multi-institutional study. All patients underwent sentinel lymph node (SLN) biopsy followed by completion level I/II axillary dissection.SLN were identified in 3,106 of 3,324 patients (93%). Axillary metastases were found in 35% and 40% of patients with infiltrating ductal carcinoma and infiltrating lobular carcinoma, respectively. Among tumor subtypes, positive nodes were found in 17% of patients with pure tubular carcinoma, 7% of patients with papillary cancer, 6% of patients with colloid (mucinous) carcinoma, 21% of patients with medullary carcinoma, and 8% of patients with DCIS with microinvasion.Patients with favorable breast cancer subtypes have a significant rate of axillary nodal metastasis. Axillary nodal staging remains important in such patients; SLN biopsy is an ideal method to obtain this staging information.

Prognostic impact of MKI67 and MMP1 in node-negative invasive ductal and invasive lobular carcinoma of the breast

21102 Background: MKI67 and MMP1 mRNA, which might reflect the biological processes of tumor proliferation and matrix degradation, respectively, have been proposed as prognostic marker in invasive carcinoma of the breast. We compared the expression of both genes in invasive lobular versus invasive ductal carcinoma, which represent the most common histological breast cancer subtypes. Methods: MKI67 and MMP1 mRNA expression was determined by microarray analysis of fresh frozen tumor tissue of 118 patients with invasive ductal and 39 patients with invasive lobular carcinoma. We compared the distribution of these markers between both histological subtypes as well as within each subtype between tumors from patients with or without subsequent distant metastasis or local recurrence by two tailed Mann-Whitney test. Results: MKI67 as marker of proliferation and MMP1 as marker of matrix degradation were significantly elevated in invasive ducal versus lobular carcinomas (p = 0.023 and p &lt; 0.0001, respectively). Furthermore, elevation of both markers were significantly associated with the occurrence of metastasis in ductal (p = 0.023 and p = 0.012) but not in lobular carcinomas (p = 0.986 and p = 0.366). In addition, no significant association was found between these markers and development of local recurrence in patients with ductal (p = 0.304 and p = 0.899) or lobular (p = 0.891 and p= 0.153) carcinomas . Conclusions: Our data suggest that differences exist between ductal and lobular carcinoma of the breast regarding both the expression and the prognostic impact of MKI67 and MMP1. Furthermore, the prognostic relevance of proliferation and matrix degradation was more important for the development of distant metastasis than for the development of local recurrence in ductal carcinoma emphasizing differences in the underlying biology of local recurrence and distant metastasis. No significant financial relationships to disclose.

Physical activity and risk of postmenopausal breast cancer defined by hormone receptor status and histology: A large prospective cohort study with 18 years of follow up

1002 Background: Physical activity is a modifiable breast cancer risk factor, perhaps mediating risk reduction through regulation of estrogen metabolism. Evidence regarding effect of physical activity is conflicting partly because breast cancer is a heterogenous constellation of different tumor subtypes with differing etiologies. No prospective study has examined the relationship between physical activity and breast cancer incidence based on ER/PR status or histological subtype. Objective: Examine effect of physical activity on breast cancer incidence based on ER/PR status and histological subtypes of breast cancer. Methods: The Iowa Women’s Health Study is a prospective cohort study of postmenopausal women (N=41,837). Physical activity was self-reported on baseline questionnaire, and three levels (high, medium and low) were defined. Breast cancer incidence, histologic subtype and ER/PR status, through 18 years of follow-up, were ascertained by linkage with the Iowa SEER Cancer Registry. Cox proportional hazards models were used to estimate multivariate relative risks (RRs) and 95% confidence intervals (CIs) of breast cancer, adjusting for other breast cancer risk factors. Results: During 554,819 person-years of follow-up, 2548 incident cases of breast cancer were observed. High physical activity was associated with decreased risk for breast cancer (RR 0.91, 95 % CI 0.81–1.01) compared to low activity. The protective effect was most marked in ER+/PR− (RR 0.66, CI 0.46–0.94), intermediate in ER−/PR− (RR 0.80, CI 0.56–1.15), weakest in ER+/PR+ (RR 0.94, CI 0.81–1.08), and elevated in ER-/PR+ (RR 1.42, CI 0.67–3.01) tumors. Higher physical activity was also associated with a decreased risk of invasive ductal/lobular carcinoma (RR 0.90, CI 0.80–1.02), but not with invasive breast cancer with a favorable histology (RR 1.19, CI 0.78–1.81). Conclusions: Higher physical activity was associated with a 10% decreased risk of breast cancer. Unexpectedly, risk reduction was most marked in PR- tumors, particularly ER+/PR-, and the more aggressive histologic forms. Further studies are needed to confirm these findings, and also evaluate other risk factors based on ER/PR status and histological subtypes. No significant financial relationships to disclose.

Relationship between Established Breast Cancer Risk Factors and Risk of Seven Different Histologic Types of Invasive Breast Cancer

Important differences in the contributions of certain exposures to the risks of ductal versus lobular breast carcinomas have been observed, but few studies have evaluated the relationships between established breast cancer risk factors and other histologic types. Information on family history of cancer and reproductive, hormonal, anthropometric, and lifestyle characteristics were collected in a multicenter population-based case-control study consisting of 3,463 ductal, 274 lobular, 261 ductal-lobular, 91 medullary, 77 tubular, 70 comedo, and 61 mucinous invasive breast carcinoma cases (ages 35-64 years, newly diagnosed 1994-1998) and 4,682 controls. Associations between each of these histologic types and various exposures were evaluated using polytomous regression. Heterogeneity in the risks of different histologic types of breast cancer was observed for three exposures: menopausal hormone use, body mass index (BMI), and alcohol consumption. Specifically, current use of unopposed estrogen was associated with a reduced risk of ductal carcinoma and increased risk of comedocarcinoma, and current use of estrogen and progestin was associated with elevated risks of ductal-lobular and tubular carcinomas. Among postmenopausal women, BMI was only inversely related to risk of ductal-lobular carcinoma, and alcohol use was only positively related to risk of lobular carcinoma. Variations in the associations between known breast cancer risk factors and risk of different breast cancer histologies were observed. Although these findings require confirmation, and the analyses of some histologic groups were limited by small sample sizes, they provide some insight into the different etiologies of various histologic subtypes of breast cancer.

Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study

IntroductionBreast cancers of different histology have different clinical and prognostic features. There are also indications of differences in aetiology. We therefore evaluated the risk of the three most common histological subtypes in relation to menopausal hormone therapy and other breast cancer risk factors.MethodsWe used a population-based case-control study of breast cancer to evaluate menopausal hormone therapy and other breast cancer risk factors for risk by histological subtype. Women aged 50 to 74 years, diagnosed with invasive ductal (n = 1,888), lobular (n = 308) or tubular (n = 93) breast cancer in Sweden in 1993 to 1995 were compared with 3,065 age-frequency matched controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for ductal, lobular, and tubular cancer.ResultsWomen who had used medium potency estrogen alone were at increased risks of both ductal and lobular cancer. Medium potency estrogen-progestin was associated with increased risks for all subtypes, but the estimates for lobular and tubular cancer were higher compared with ductal cancer. We found OR 5.6 (95% CI 3.2–9.7) for lobular cancer, OR 6.5 (95% CI 2.8–14.9) for tubular cancer and OR 2.3 (95% CI 1.6–3.3) for ductal cancer with ≥5 years use of medium potency estrogen-progestin therapy. Low potency oral estrogen (mainly estriol) appeared to be associated with an increased risk for lobular cancer, but the association was strongest for short-term use. Reproductive and anthropometric factors, smoking, and past use of oral contraceptives were mostly similarly related to the risks of the three breast cancer subtypes. Recent alcohol consumption of > 10 g alcohol/day was associated with increased risk only for tubular cancer (OR 3.1, 95% CI 1.4–6.8).ConclusionMenopausal hormone therapy was associated with increased risks for breast cancer of both ductal and lobular subtype, and medium potency estrogen-progestin therapy was more strongly associated with lobular compared with ductal cancer. We also found medium potency estrogen-progestin therapy and alcohol to be strongly associated with tubular cancer. With some exceptions, most other risk factors seemed to be similarly associated with the three subtypes of breast cancer.

DIFFERENTIATION OF TUMOURS OF DUCTAL AND LOBULAR ORIGIN: I. PROTEOMICS OF INVASIVE DUCTAL AND LOBULAR BREAST CARCINOMAS

The vast majority of invasive breast tumors are ductal and lobular breast carcinomas. Despite the many similarities, some clinical follow-up data and the patterns of metastases suggest that these histological subtypes of breast cancer are biologically distinct. Few papers, however, describe immunohistochemical markers useful for differentiation of these carcinomas. Many investigations suggest that E cadherin protein expression is lost in lobular but not in ductal carcinoma. The absence of E-CD, as a partial loss of epithelial differentiation, may account for the extended spread of lobular carcinoma in situ and the peculiar diffuse invasion mode of invasive lobular carcinoma. Some investigations report the significance of E-CD associated proteins alpha-, beta-, gamma-catenin expression, as well as the usefulness of cytokeratins 5, 6, 8, 7 and thrombospondin in differentiating histological types of breast invasive carcinomas. Several reports have suggested the possibility that invasive ductal and lobular cancers differ with respect to expression of antigens involved in proliferation and cell cycle regulation. It has been shown that vascular endothelial growth factor expression, also the expression of maspin, a tumour suppressor gene product, is higher in ductal, than in lobular carcinoma. Expression of NKX3.1, a member of the NK-class of homeodomain, is highly restricted and is found primarily in lobular carcinoma. Some histological and immunohistochemical characteristics of pleomorphic lobular carcinoma are also discussed.

An overview of menopausal oestrogen–progestin hormone therapy and breast cancer risk

Results from the Women's Health Initiative (WHI) trial support findings from observational studies that oestrogen–progestin therapy (EPT) use is associated with an increase in breast cancer risk. We conducted a meta-analysis using EPT-specific results from the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) pooled analysis and studies published since that report to obtain an overview of EPT use and breast cancer risk. We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use. We estimate that overall, EPT results in a 7.6% increase in breast cancer risk per year of use. The risk was statistically significantly lower in US studies than in European studies – 5.2 vs 7.9%. There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT. We observed no overall difference in risk for lobular vs ductal carcinoma but did observe a slightly higher risk for current vs past EPT use.

Fine-needle aspiration cytology of glycogen-rich carcinoma of breast: Report of a case and review of literature

Glycogen-rich carcinoma (GRC) of the breast is a rare histological subtype of breast cancer having a poor prognosis. There are very few case reports describing the cytological features of GRC on fine-needle aspiration cytology (FNAC). In this report we present the case of a 34-yr-old woman who underwent FNAC of a clinically palpable breast lump. The aspirate was cellular showing tumor cells in groups, clusters and lying singly. The tumor cells had abundant eosinophilic, finely granular to vacuolated cytoplasm with moderate to marked nuclear pleomorphism. With a cytological diagnosis of carcinoma, a wide local excision was performed. On histology a diagnosis of GRC was made with the tumor cells showing abundant glycogen. The presence of cells with abundant granular to finely vacuolated cytoplasm in a case of breast carcinoma, should point toward the possibility of GRC and other clear cell tumors of the breast. Demonstration of glycogen is required to make a definite diagnosis on cytology.

Advances in Screening, Diagnosis, and Treatment of Breast Cancer

Advances in Screening, Diagnosis, and Treatment of Breast Cancer

Histopathology of breast cancer among African-American women.

Although the overall incidence of breast cancer in African-American women is lower than in white women, African-American women younger than 50 years old have a higher incidence of breast cancer than white women. African-American women with breast cancer have a poorer survival rate than white women and are more likely to die of breast cancer in almost every age group. To explain this disparity, we studied a substantial body of literature that reported a biologic difference in the tumors found in African-American and white women. Specifically, more aggressive histopathologic patterns have been described among African-American patients with breast cancer when compared with white women. In addition, there are data that support an ethnicity-related variation in the expression of breast tumor hormonal markers. The objective of this study was to critically evaluate the existing published data on the histologic features of breast cancer to determine whether breast cancer in African-American women is a histologically more aggressive disease than in white women. We conclude that the aggressive tumor histology reported in African-American women has not been analyzed carefully with respect to the age of the patient at the time of diagnosis and the stage of disease at presentation. Furthermore, there is a need for central pathology review using accepted, published criteria for diagnosis of uncommon and controversial histologic subtypes of breast cancer.

Frequency of sentinel lymph node metastases in patients with favorable breast cancer histologic subtypes

BackgroundThe need for axillary nodal staging in favorable histologic subtypes of breast cancer is controversial. MethodsPatients with clinical stage T1-2, N0 breast cancer were enrolled in a prospective, multi-institutional study. All patients underwent sentinel lymph node (SLN) biopsy followed by completion level I/II axillary dissection. ResultsSLN were identified in 3,106 of 3,324 patients (93%). Axillary metastases were found in 35% and 40% of patients with infiltrating ductal carcinoma and infiltrating lobular carcinoma, respectively. Among tumor subtypes, positive nodes were found in 17% of patients with pure tubular carcinoma, 7% of patients with papillary cancer, 6% of patients with colloid (mucinous) carcinoma, 21% of patients with medullary carcinoma, and 8% of patients with DCIS with microinvasion. ConclusionsPatients with favorable breast cancer subtypes have a significant rate of axillary nodal metastasis. Axillary nodal staging remains important in such patients; SLN biopsy is an ideal method to obtain this staging information.

Prolonged Survival in a Case of Small Cell Carcinoma of the Breast

: Small cell carcinoma of the breast is a rare his-tologic subtype of breast cancer. In the neuroendocrine features it manifests, it resembles small cell carcinoma in other sites histologically and immunohistochemically. Despite the usual aggressive behavior of small cell carcinoma of the breast, the present patient illustrates that some patients do experience longer survival than others. This patient was 62 years old at presentation, and had one positive lymph node. She expired 29 months later with diffuse metastases; however, she lived much longer than comparable node-positive patients with this neoplasm. Her prolonged survival may correlate with adjuvant studies such as flow cytometry, which in the present patient showed a diploid population of cells with 5% S-phase fraction.

Epidermal growth factor receptor status of histological sub-types of breast cancer.

The histological breakdown of a consecutive series of 264 surgically resected malignant lesions of the breast was studied. Oestrogen and epidermal growth factor receptor status was quantified and presented along with size and lymph node status of the non-ductal lesions. Those non-ductal tumours containing EGF receptors have all recurred within two years of resection. Twenty-one percent of the lobular carcinomas contained EGF receptors compared to 34% of ductal carcinomas. EGF receptor status appeared to be associated with an increased risk of early recurrence and death whatever the histological sub-type of the breast cancer.

Effect of age at first childbirth on risk of developing specific histologic subtype of breast cancer.

Epidemiologic variables related to breast cancer risk were assessed in a case-control study of 332 women with breast carcinoma and 1353 comparison women. Risk factors for breast cancer as a whole included nulliparity, late age at first childbirth, early age at menarche, late age at menopause, personal history of benign breast disease, family history of breast cancer, and among postmenopausal women, body weight. These risk factors were then analyzed with respect to histologic subtype of breast cancer involved, i.e., duct-derived or lobular tumors, to determine whether the association between any of the risk factors and breast cancer varied according to histopathologic subtype. Histologic subtype for the 316 cases reviewed included 284 duct cancers and 32 lobular carcinomas. Although slight differences were noted among some of the risk factors and the variety of cancer, none of the differences was marked except for the variable age at birth birth. For ductal carcinoma, the risk was highest among nulliparous women and decreased the younger a woman was at the time she gave birth to her first child. The risk of infiltrating lobular carcinoma, however, was lowest among nulliparous females or those who had given birth at a young age and increased the older a woman was when she gave birth to her first child.